Currently, over five million Americans suffer with Alzheimer’s disease (AD). In the absence of a cure, this number could increase to 13.8 million by 2050. A critical goal of biomedical research is to establish indicators of AD during the preclinical stage (i.e. biomarkers) allowing for early diagnosis and intervention. Numerous advances have been made in developing biomarkers for AD using neuroimaging approaches. These approaches offer tremendous versatility in terms of targeting distinct age-related and pathophysiological mechanisms such as structural decline (e.g. volumetry, cortical thinning), functional decline (e.g. fMRI activity, network correlations), connectivity decline (e.g. diffusion anisotropy), and pathological aggregates (e.g. amyloid and tau PET). In this review, we survey the state of the literature on neuroimaging approaches to developing novel biomarkers for the amnestic form of AD, with an emphasis on combining approaches into multimodal biomarkers. We also discuss emerging methods including imaging epigenetics, neuroinflammation, and synaptic integrity using PET tracers. Finally, we review the complementary information that neuroimaging biomarkers provide, which highlights the potential utility of composite biomarkers as suitable outcome measures for proof-of-concept clinical trials with experimental therapeutics.

Introduction Loss of entorhinal cortex (EC) layer II neurons represents the earliest Alzheimer's disease (AD) lesion in the brain. Research suggests differing functional roles between two EC subregions, the anterolateral EC (aLEC) and the posteromedial EC (pMEC). Methods We use joint label fusion to obtain aLEC and pMEC cortical thickness measurements from serial magnetic resonance imaging scans of 775 ADNI‐1 participants (219 healthy; 380 mild cognitive impairment; 176 AD) and use linear mixed‐effects models to analyze longitudinal associations among cortical thickness, disease status, and cognitive measures. Results Group status is reliably predicted by aLEC thickness, which also exhibits greater associations with cognitive outcomes than does pMEC thickness. Change in aLEC thickness is also associated with cerebrospinal fluid amyloid and tau levels. Discussion Thinning of aLEC is a sensitive structural biomarker that changes over short durations in the course of AD and tracks disease severity—it is a strong candidate biomarker for detection of early AD.

Introduction: Loss of entorhinal cortex (EC) layer II neurons represents the earliest AD lesion in the brain. Research suggests differing functional roles between two EC subregions, the anterolateral EC (aLEC) and the posteromedial EC (pMEC). Methods: We use joint label fusion to obtain aLEC and pMEC cortical thickness measurements from serial MRI scans of 775 ADNI-1 participants (219 healthy; 380 MCI; 176 AD) and use linear mixed-effects models to analyze longitudinal associations between cortical thickness, disease status and cognitive measures. Results: Group status is reliability predicted by aLEC thickness, which also exhibits greater associations with cognitive outcomes than does pMEC thickness. Change in aLEC thickness is also associated with CSF amyloid and tau levels. Discussion: Thinning of aLEC is a sensitive structural biomarker that changes over short durations in the course of AD and tracks disease severity; it is a strong candidate biomarker for detection of early AD.

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Introduction:We tested whether Alzheimer's disease (AD) pathology predicts memory deficits in non-demented older adults through its effects on medial temporal lobe (MTL) subregional volume. Methods: Thirty-two, non-demented older adults with cerebrospinal fluid (CSF) (amyloid-beta [Aβ] 42 /Aβ 40 , phosphorylated tau [p-tau] 181 , total tau [t-tau]), positron emission tomography (PET; 18F-florbetapir), high-resolution structural magnetic resonance imaging (MRI), and neuropsychological assessment were analyzed. We examined relationships between biomarkers and a highly granular measure of memory consolidation, retroactive interference (RI). Results: Biomarkers of AD pathology were related to RI. Dentate gyrus (DG) and CA3 volume were uniquely associated with RI, whereas CA1 and BA35 volume were related to both RI and overall memory recall. AD pathology was associated with reduced BA35, CA1, and subiculum volume. DG volume and Aβ were independently associated with RI, whereas CA1 volume mediated the relationship between AD pathology and RI. Discussion: Integrity of distinct hippocampal subfields demonstrate differential relationships with pathology and memory function, indicating specificity in vulnerability and contribution to different memory processes.